Methods for treating osteoarthritis pain

ABSTRACT

Methods for alleviating osteoarthritis-associated symptoms by selecting a treatment-eligible patient and local administration of a clostridial derivative, such as a botulinum toxin, to an osteoarthritis-affected site are disclosed herein.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/840,923, filed Aug. 31, 2015, which claims the benefit of U.S.Provisional Application Ser. Nos. 62/049,759, filed Sep. 12, 2014, and62/052,833, filed Sep. 19, 2014, all incorporated herein entirely byreference.

FIELD

The present disclosure relates to methods for treatment of arthritis. Inparticular, the present disclosure relates to methods of treatingosteoarthritis-associated symptoms, such as pain, using a clostridialderivative.

BACKGROUND

Arthritis is one of the most prevalent chronic health problems and oneof the most common causes of disability in America. It affects over 45million adults in the United States. This number is anticipated to riseto 60 million, or 18% of the population, by 2020. There are more than127 different types of arthritis as defined by the Arthritis Foundation,including osteoarthritis, rheumatoid arthritis, psoriatic arthritis,septic arthritis and related autoimmune diseases. Regardless of the typeof arthritis, common symptoms for all arthritis disorders include variedlevels of pain, swelling, functional limitation and joint stiffness.Arthritic disorders such as lupus and rheumatoid can also affect otherorgans in the body.

The goals of current therapies for arthritis, including osteoarthritis,are to alleviate pain and other related arthritis associated symptoms.Current therapies for managing osteoarthritis pain include oralanalgesics or corticosteroids, localized treatments with topicalanalgesics (e.g., NSAIDs, capsaicin), intra-articular injections ofcorticosteroids or viscosupplements. Oral analgesics have substantiallimitations because they may not provide sufficient pain relief andoften produce intolerable side effects, for example, gastrointestinalbleeding and renal toxicity for regular NSAIDS users, addiction orbreathing suppression for opioids, and adverse drug interactions.Localized corticosteroid injections may reduce pain for a short period(1-3 weeks), but have long term side effects, including cartilage breakdown, Cushing's syndrome; furthermore they are intolerable to patientswith diabetic mellitus. Viscosupplement administration, such ashyaluronic acid, while well-tolerated, is not always effective. Thus,there is a need for safe, effective alternative therapies for treatmentof osteoarthritis pain.

SUMMARY OF THE INVENTION

Aspects of the present disclosure provide a method for treating oralleviating at least one symptom of arthritis, such as osteoarthritis.In some aspects, the present disclosure provides a method for treatingor alleviating at least one osteoarthritis-associated symptom, such asOA pain, in a patient in need thereof.

In some aspects, the present disclosure provides a method for treatingor alleviating OA-associated pain, the method comprises selecting atreatment-susceptible or treatment-eligible patient, administering tothe treatment-eligible patient a therapeutically effective amount of aclostridial derivative to an osteoarthritis-affected site of thetreatment-susceptible patient, thereby treating or alleviating theOA-associated pain. In some embodiments, the selecting step comprisescategorizing the pain that a patient experiences at theosteoarthritis-affected site, and identifying the patient astreatment-susceptible/eligible. In some embodiments, the identifyingstep comprises categorizing the OA-associate pain as nociceptive ornon-nociceptive, such as neuropathic pain. In some embodiments, theselecting step comprises selecting a patient having nociceptive pain. Insome embodiments, the selecting step comprises providing the patient aplurality of questions relating to characteristics of the OA-associatedpain that the patient perceives, receiving numerical responses to theplurality of questions by the patient, calculating a score based on thenumerical responses, comparing the score to a cut-off value; anddetermining whether the patient is treatment-eligible.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are presented to illustrate aspects and featuresof embodiments of the present invention.

FIG. 1 shows the mean change from baseline in Daily Worst Pain Intensityper 14-Day Period in the overall or safety population after treatmentwith an exemplary clostridial derivative (onabotulinumtoxinA) or with aplacebo in patients with primary knee osteoarthritis. Baseline refers tothe Pain Intensity recorded the last 14 days preceding randomization.Each week-X refers to the 14 day period ending with that post-treatmentweek;

FIG. 2 shows the mean change from baseline in WOMAC Pain Score in theoverall safety population over 12-week period after treatment with theexemplary clostridial derivative or with the placebo in patients withprimary knee osteoarthritis. Baseline refers to the Pain Score recordedon Day 1 prior to treatment;

FIGS. 3A and 3B show the mean change from baseline in Daily Worst PainIntensity in a nociceptive pain subgroup (3A) and the overall safetypopulation (3B) over 12-week period after treatment with the exemplaryclostridial derivative or with the placebo in patients with primary kneeosteoarthritis;

FIGS. 4A and 4B show the mean change from baseline in WOMAC pain scorein the nociceptive pain subgroup (4A) and the overall safety population(4B) over 12-week period after treatment with the exemplary clostridialderivative or with the placebo in patients with primary kneeosteoarthritis;

FIGS. 5A and 5B show the numbers of Patient-GIC Responders in thenociceptive pain subgroup (5A) and the overall safety population (5B)over 12-week period after treatment with the exemplary clostridialderivative or with the placebo in patients with primary kneeosteoarthritis; and

FIGS. 6A and 6B show the Rescue Medication Cumulative Count in thenociceptive pain subgroup (6A) and the overall safety population (6B)over 12-week period after treatment with the exemplary clostridialderivative or with the placebo in patients with primary kneeosteoarthritis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

As used herein, the words or terms set forth below have the followingdefinitions:

“About” or “approximately” as used herein means within an acceptableerror range for the particular value as determined by one of ordinaryskill in the art, which will depend in part on how the value is measuredor determined, (i.e., the limitations of the measurement system). Forexample, “about” can mean within 1 or more than 1 standard deviations,per practice in the art. Where particular values are described in theapplication and claims, unless otherwise stated, the term “about” meanswithin an acceptable error range for the particular value.

“Administration”, or “to administer” means the step of giving (i.e.administering) a botulinum toxin to a subject, or alternatively asubject receiving a pharmaceutical composition. The present method canbe performed via administration routes including intramuscular,non-intramuscular, intra-articular, extra-articular, peri-articular,intradermal, subcutaneous administration, topical administration (usingliquid, cream, gel or tablet formulation), intrathecal administration,intraperitoneal administration, intravenous infusion, implantation (forexample, of a slow-release device such as polymeric implant orminiosmotic pump, or combinations thereof.

“Alleviating” means a reduction in arthritis associated structuraldeterioration. Thus, alleviating includes some reduction, significantreduction, near total reduction, and total reduction. An alleviatingeffect may not appear clinically for between 1 to 7 days afteradministration of a clostridial derivative to a patient or sometimethereafter.

“Botulinum toxin” means a neurotoxin produced by Clostridium botulinum,as well as a botulinum toxin (or the light chain or the heavy chainthereof) made recombinantly by a non-Clostridial species. The term“botulinum toxin”, as used herein, encompasses the botulinum toxinserotypes A, B, C₁, D, E, F and G, and their subtypes and any othertypes of subtypes thereof, or any re-engineered proteins, analogs,derivatives, homologs, parts, sub-parts, variants, or versions, in eachcase, of any of the foregoing. “Botulinum toxin”, as used herein, alsoencompasses a “modified botulinum toxin”. Further “botulinum toxin” asused herein also encompasses a botulinum toxin complex, (for example,the 300, 600 and 900 kDa complexes), as well as the neurotoxic componentof the botulinum toxin (150 kDa) that is unassociated with the complexproteins.

“Clostridial derivative” refers to a molecule which contains any part ofa clostridial toxin. As used herein, the term “clostridial derivative”encompasses native or recombinant neurotoxins, recombinant modifiedtoxins, fragments thereof, a Targeted vesicular Exocytosis Modulator(TEM), or combinations thereof.

“Clostridial toxin” refers to any toxin produced by a Clostridial toxinstrain that can execute the overall cellular mechanism whereby aClostridial toxin intoxicates a cell and encompasses the binding of aClostridial toxin to a low or high affinity Clostridial toxin receptor,the internalization of the toxin/receptor complex, the translocation ofthe Clostridial toxin light chain into the cytoplasm and the enzymaticmodification of a Clostridial toxin substrate.

“Effective amount” as applied to the biologically active ingredientmeans that amount of the ingredient which is generally sufficient toinduce a desired change in the subject.

“Implant” means a controlled release (e.g., pulsatile or continuous)composition or drug delivery system. The implant can be, for example,injected, inserted or implanted into a human body.

“Intra-articular injection” refers to an injection directly into a jointor into a portal.

“Extra-articular injection” refers to an injection outside of a jointspace.

“Nociceptive pain” is defined as pain that arises from actual orpotential damage to non-neuronal tissue and is due to the physiologicalactivation of nociceptors.

“Neuropathic pain” is defined as pain arising as a direct consequence ofa lesion or disease of the somatosensory nerve system.

“Peri-articular injection” refers to an injection to an area around ajoint.

“Local administration” means administration of a clostridial derivativeto or to the vicinity of an arthritis-affected site in a patient by anon-systemic route. Thus, local administration excludes systemic routesof administration, such as intravenous or oral administration.

“Peripheral administration” means administration to a location away froma symptomatic location, as opposed to a local administration.

“TEMs”, abbreviated for Targeted Exocytosis Modulators are retargetedendopeptidases that direct the catalytic activity of the light chain tospecific types of neuronal cells or to target cells that were notaffected by botulinum toxins expanding the beneficial clinical effect ofinhibition of exocytosis in several human diseases.

“Treating” or “treatment” means to alleviate (or to eliminate) anundesirable condition, for example cartilage deterioration, eithertemporarily or permanently.

“Therapeutically effective amount” refers to an amount sufficient toachieve a desired therapeutic effect. The therapeutically effectiveamount usually refers to the amount administered per injection site perpatient treatment session, unless indicated otherwise.

“Treatment-susceptible”, used interchangeably with “treatment-eligible”refers to a patient or a group which is deemed eligible to receive thetreatment after the symptoms, such as pain, of the patient or the grouphave been categorized or classified. In some embodiments,treatment-eligible refers to a patient or group of patient whose painhas been classified as nociceptive pain.

“Treatment-uncertain”, refers to a patient or a group which may or maynot be eligible to receive the treatment after the symptoms, such aspain, of the patient or the group have been categorized or classified.In some embodiments, treatment-uncertain refers to a patient or group ofpatients whose pain has been classified as non-nociceptive pain, and thepain is classified as possibly neuropathic pain. In some embodiments,after the classification of nociceptive versus non-nociceptive, anadditional categorizing step may be required to decide whether thepatient is eligible for treatment.

“Treatment-unsusceptible”, used interchangeably with“treatment-ineligible” refers to a patient or a group which is notdeemed eligible to receive the treatment after the symptoms, such aspain, of the patient or the group have been categorized or classified.In some embodiments, treatment-ineligible refers to a patient or groupof patient whose pain has been classified as non-nociceptive pain. Insome embodiments, the treatment-ineligible refers to a patientclassified as having neuropathic pain.

In some aspects, the present disclosure provides a method for treatingor alleviating arthritis-associated symptoms, including osteoarthritis(OA)-associated pain, rheumatoid arthritis (RA)-associated pain orpsoriatic arthritis-associated pain in a patient.

Arthritis

Arthritis is a form of joint disorder that involves inflammation of oneor more joints. Normal articular cartilage consists of an extensivehydrated extracellular matrix. The matrix consists mainly of collagenand proteoglycans, principally aggrecan, which is large and aggregateswith hyaluronic acid. Embedded in the extracellular matrix are thechondrocytes, which regulate the synthesis and degradation of thearticular cartilage. In normal articular cartilage, the extracellularmatrix is constantly being degraded and synthesized. Collagen andcartilage proteoglycans are degraded by various proteinases, includingmetalloproteinases, and collagenages. Under normal circumstances, theactivation of these degradative enzymes is held in check by inhibitors,such as tissue inhibitor of metalloproteinases (TIMPs) and plasminogenactivator inhibitor-7 (PAI-7). The balance of metalloproteinases (MMPs)and inhibitors of metalloproteinases (TIMPs) is important to maintainthe normal turnover of the extracellular matrix. Under pathologicalconditions such as for example in Osteoarthritis and Rheumatoidarthritis, mechanical and shear stress, inflammatory cytokines (e.g.,IL-1, IL-6 and tumor necrosis factor-α) and/or growth factors disruptthis balance and promote the synthesis of MMPs and inhibit theexpression of TIMPs. Thus, collagen and aggrecan degradation willoutweigh the synthesis and deposition by chondrocytes, which ultimatelyresults in cartilage defect. Inflammation can occur secondary tostructural damage as in osteoarthritis or is the main cause to incurarthritis with subsequent structural damage as in rheumatoid arthritis.

Osteoarthritis (OA)

Osteoarthritis (OA) is the most common form of arthritis and a leadingcause of chronic disability. It can affect both the larger and thesmaller joints of the body, including the hands, feet, back, hip, kneeand spine. OA is a multifactorial disease, characterized by joint pain,tenderness, limitation of movement, crepitus, occasional effusion, wearor tear of cartilage, wear or tear of meniscus, wear or tear ofligament, subchondrial bone lesion, capsule damage and/or hyperplasia ofthe synovial membrane. Progression of OA is marked by destruction of thejoint cartilage, sclerosis or cyst formation of underlying bone, jointspace narrowing and formation of osteophytes at the joint margin. KneeOA is a highly prevalent condition that affects upwards of 89 millionpeople worldwide. Approximately 12.1% of people older than 60 years havesymptomatic knee OA. Pain is the most prominent symptom of knee OA andis the primary reason patients seek medical help. Knee OA is oftenprogressive, and currently there is no known cure. The primary goals fortreatment include relieving pain, maintaining/improving function andreducing disability. Despite the availability of various pharmacologicagents, symptom management for patients suffering from knee pain andfunctional disability due to OA continues to be a problem for many dueto ineffectiveness and/or intolerability of many of these agents in thispatient population. Thus, there is a high unmet medical need for moreeffective and well-tolerated treatments.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis (RA) is an autoimmune disease that results in achronic, systemic inflammatory disorder that may affect many tissues andorgans, but principally attacks flexible (synovial) joints. It can be adisabling and painful condition, which can lead to substantial loss offunctioning and mobility if not adequately treated. Joint cartilage lossand other structural damage are subsequent to inflammatory response atthe involved joints. Once cartilage lesion occurs, RA will have asimilar disease progression as OA even after the primary inflammationcause is under control.

Botulinum Toxin

Botulinum neurotoxins (BoNTs) such as, for example, BoNT/A, BoNT/B,etc., act on the nervous system by blocking the release ofneurosecretory substances such as neurotransmitters at the nerveendings. The action of BoNT is initiated by its binding to a receptormolecule on the cell surface, then the toxin-receptor complex undergoesendocytosis. Once inside the cell, BoNT cleaves exocytotic specificproteins responsible for neurotransmitter docking and release from thecell known as the SNARE proteins (soluble N-ethylmaleimide-sensitivefactor attachment protein receptor). The resulting transientchemodenervation has been utilized medically to block motorneurotransmission at the neuromuscular junction leading to a variety oftherapeutic applications.

Of the existing serotypes, Botulinum toxin type A is one of the mostlethal natural biological agents known to man. About 50 picograms of acommercially available botulinum toxin type A (purified neurotoxincomplex, available from Allergan, Inc., of Irvine, Calif. under thetrade name BOTOX® in 100 unit vials) is a LD₅₀ in mice (i.e. 1 unit).One unit of BOTOX® contains about 50 picograms (about 56 attomoles) ofbotulinum toxin type A complex. One unit (U) of botulinum toxin isdefined as the LD₅₀ upon intraperitoneal injection into female SwissWebster mice weighing 18 to 20 grams each.

Botulinum toxin has become widely investigated for its therapeuticpotential in the treatment of a variety of neuro-muscular disordersincluding: blepharospasm, spasmodic dysphonia, Strabismus, hemifacialspasm, and adult onset spasmodic torticollis. (Simpson, 1981; Habermann,1989; Jankovic and Brin, 1991; Borodic et al., 1991; Hambleton, 1992;Schantz and Johnson, 1992; Valtorta and Arslan 1993). Intramuscularinjection of nanogram quantities of purified botulinum toxin results inthe toxin binding to presynaptic cholinergic nerve terminals andinhibits the release of acetylcholine and thus decreases muscleactivity. The result is relaxation of the tonically contracted muscleand thus relaxation of the intended muscle or muscle group.

Botulinum toxin has been described in a method for treatingosteoarthritis associated pain (see e.g. U.S. Pat. No. 8,470,337);wherein the toxin is administered by intramuscular injections into thesplenius capitis and temporalis muscles in order to alleviate theosteoarthritis associated pain.

The present disclosure provides a method for treating or alleviatingosteoarthritis associated-symptoms in a patient in need thereof. In someembodiments, the osteoarthritis associated-symptom is joint pain.

In some aspects, the present disclosure provides a method for treatingor alleviating OA-associated pain, the method comprises selecting atreatment-susceptible or treatment-eligible patient, and administeringto the treatment-eligible patient a therapeutically effective amount ofa clostridial derivative to an osteoarthritis-affected site of thepatient, thereby treating or alleviating the OA-associated pain. In someembodiments, the treatment-eligible patient is one whose pain has beencategorized as nociceptive.

In some embodiments, the selecting step comprises categorizing the painthat a patient experiences at an osteoarthritis-affected site.

In some embodiments, the categorizing step comprises classifying thepain that the patient experiences as nociceptive or non-nociceptive,such as neuropathic or possibly neuropathic.

In some embodiments, the categorizing step comprises providing to thepatient a plurality of questions, the plurality of questions relating tothe characteristics of the pain that the patient perceives. In someembodiments, the characteristics comprise the gradation of pain, thepain course pattern, the pain radiating pattern, or combinationsthereof. In some embodiments, the plurality of questions comprisenumerical values which the patient chooses to rate the characteristicsof the pain. In some embodiments, one or more questions compriseselecting a picture that best describes the course of the pain. In someembodiments, the picture has a numerical value assigned. In someembodiments, at least one question comprises a confirmation ordisconfirmation question, wherein the patient can reply withconfirmation (yes) or disconfirmation (no). In some embodiments, theconfirmation and disconfirmation replies are each assigned each anumerical value.

In some embodiments, the categorizing step further comprises receivingnumerical responses to the plurality of questions from the patient,calculating a score based on the numerical responses from the patient.

In some embodiments, the selecting step comprises identifying thepatient as treatment-susceptible/eligible ortreatment-unsusceptible/ineligible. In some embodiments, thetreatment-eligible patient is categorized as having nociceptive pain. Insome embodiments, the treatment-ineligible patient is categorized ashaving non-nociceptive pain, such as neuropathic pain or possiblyneuropathic pain.

In some embodiments, the identifying step comprises comparing the scorecalculated in the categorizing step with a cut-off value. In someembodiments, the patient is identified as treatment-eligible if thescore is smaller or equal to the cut-off value. In some embodiments, thepatient is identified as treatment-ineligible if the score is greaterthan the cut-off value. In alternative embodiments, the patient isidentified as treatment-eligible if the score is greater or equal to thecut-off value, or as treatment-ineligible if the score is smaller thanthe cut-off value.

In some embodiments, the selecting step comprises identifying thepatient as treatment-eligible, treatment-ineligible ortreatment-uncertain. In some embodiments, the treatment-eligible patientis one categorized as having nociceptive pain. In some embodiments, thetreatment-ineligible patient is one categorized as having neuropathicpain. In some embodiments, the treatment-uncertain patient is one thatis categorized as having non-nociceptive pain, which is likely orprobably neuropathic pain.

In some embodiments, the selecting step comprises comparing the scorecalculated in the categorizing step with two cut-off values. In someembodiments, the patient is identified as treatment-eligible if thescore is smaller or equal to a first cut-offvalue. In some embodiments,the patient is identified as treatment-ineligible group if the score isgreater or equal to a second cut-off value. In some embodiments, thepatient is identified as treatment-uncertain if the score is greaterthan the first cut-off value and smaller than the second cut-off value.In alternative embodiments, the patient is identified astreatment-eligible if the score is greater or equal to the first cut-offvalue, as treatment-ineligible if the score is smaller than the secondcut-off value, or treatment uncertain if the score is smaller than thefirst cut-off value and larger than the second cut-off value. In someembodiments, if the patient is identified as treatment-uncertain,additional assessment is carried out to further determine whether thepatient is treatment-eligible or ineligible. In some embodiments, thepresent method comprises selecting a treatment-eligible patient. In someembodiments, the present method comprises excluding patients that arenot identified as treatment-eligible, such as treatment-ineligible ortreatment-uncertain.

In some embodiments, the present method comprises using a questionnaireto identify a treatment-eligible patient. Table 1 illustrates anexemplary and non-limiting questionnaire that can be used with thepresent method.

TABLE 1 Exemplary questionnaire to classify patients astreatment-eligible or treatment ineligible. Item Score Gradation ofpain* *Do you suffer from a burning sensation 0-5 (e.g. stingingnettles) in the marked areas? *Do you have a tingling or prickling 0-5sensation in the area of your pain (like crawling ants or electricaltingling)? *Is light touching (clothing, a blanket) 0-5 in this areapainful? *Do you have sudden pain attacks in the 0-5 area of your pain,like electric shocks? *Is cold or heat (bath water) in this 0-5 areaoccasionally painful? *Do you suffer from a sensation of 0-5 numbness inthe areas that you marked? *Does slight pressure in this area, e.g. 0-5with a finger, trigger pain? Pain course pattern Please Select thepicture that best describes the course of your pain:

 Persistent pain with slight fluctuations  0

 Persistent pain with pain attacks −1

 Pain attacks without pain between them +1

 Pain attacks with pain between them +1 Radiating pain Does your painradiate to other regions of your body? Yes/No +2/0 *For each question:never, 0; hardly noticed, 1; slightly, 2; moderately, 3; strongly, 4;very strongly, 5 Questions used to document pain, but which were notused in the scoring, are not shown

In an exemplary and non-limiting embodiment, the present methodcomprises using a PainDETECT questionnaire (shown in Table 1) to selector identify a treatment-eligible patient. In some embodiments, thepresent method comprises using the PainDETECT questionnaire to classifypatients into nociceptive or non-nociceptive groups.

In one exemplary embodiment, the PainDETECT questionnaire is a patientself-administered questionnaire. The questionnaire has a total minimumscore of 1 and a total maximum score of 38, which is calculated from thesum of scores to nine questions, the questions relating to the gradationof pain, the pain course pattern, the pain radiating pattern, orcombinations thereof.

In some embodiments, the patient is identified: (1) as havingnociceptive pain if the total score to the questionnaire is smaller orequal to a cut-off point; or (2) as having non-nociceptive pain group ifthe total score to the questionnaire is greater than the cut-off point.The cut-off value can be any number within the total minimum score andthe total maximum score. In some embodiments, the cut-off value is 12.In alternative embodiments, the patient is identified: (1) as havingnociceptive pain if the total score to the questionnaire is smaller orequal to a first cut-off point; (2) as having non-nociceptive pain groupif the total score to the questionnaire is greater or equal than asecond cut-off point; or (3) as having possibly non-nociceptive pain ifthe total score is greater than the first cut-off point and smaller thanthe second cut-off point. The cut-off value can be any number within thetotal minimum score and the total maximum score. In some embodiments,the first cut-off value is 12 and the second cut-off value is 19. Inalternative embodiments, the first cut-off value and the second cut-offvalues can be different numbers.

In some embodiments, subsequent to the selecting step, the presentmethod comprises administering to the treatment-eligible patient atherapeutically effective amount of a clostridial derivative to anosteoarthritis-affected site.

In some embodiments, the arthritis-affected site orosteoarthritis-affected site includes a knee joint, a hip joint, a handjoint, a shoulder joint, an ankle joint, a foot joint, an elbow joint, awrist joint, a sacroiliac joint, a spine joint, or combinations thereof.

In some embodiments, the clostridial derivative is administered directlyinto a joint cavity or structural components surrounding the jointcavity, or both. In some embodiments, the administration of theclostridial derivative is by intra-articular, extra-articular,peri-articular injections, or combinations thereof. In one embodiment,the clostridial derivative is administered in the patellofemoral spaceof the study knee, using an aseptic and ultrasound guided technique.

Intra-articular administration sites include the cavity of the affectedjoint, a medial supra-patellar portal, medial or lateral mid-patellarportals and medial or lateral infra-patellar portals, or combinationsthereof. Peri-articular delivery sites include: infra-patellar fat pad,quadriceps fat pad, anterior suprapatellar fat pad, subcutaneous space,subcutaneous bursa, intra-articular bursa, cruciate ligaments ifpresent, menisci if present, medial and/or lateral collateral ligaments,capsule, periosteum in the joint, bone morrow; tendons surrounding thejoint; intra-venous infusion. In alternative embodiments, theadministration route is by intramuscular, non-intramuscular,intradermal, subcutaneous administration, intrathecal administration,intraperitoneal administration, implantation, or combinations thereof.

Intra-articular administration of the clostridial derivative to theaffected site can be guided by fluoroscopy or ultrasonography, as wellknown to one of ordinary skills in the art. For deeper joints such asthe hip, imaging guidance is crucial. To limit the risk of inaccurateneedle placement, the present method further comprises aspiring synovialfluid within the joint cavity prior to administration of the clostridialderivative.

In some embodiments, the clostridial derivative of the present methodincludes a native, recombinant clostridial toxin, recombinant modifiedtoxin, fragments thereof, targeted exocytosis modulators (TEMs), orcombinations thereof. In some embodiments, the clostridial derivative isa botulinum toxin. In alternative embodiments, the clostridialderivative is a TEM.

In some embodiments, the botulinum neurotoxin can be a modifiedneurotoxin, that is a botulinum neurotoxin which has at least one of itsamino acids deleted, modified or replaced, as compared to a nativetoxin, or the modified botulinum neurotoxin can be a recombinantproduced botulinum neurotoxin or a derivative or fragment thereof. Incertain embodiments, the modified toxin has an altered cell targetingcapability for a neuronal or non-neuronal cell of interest. This alteredcapability is achieved by replacing the naturally-occurring targetingdomain of a botulinum toxin with a targeting domain showing a selectivebinding activity for a non-botulinum toxin receptor present in anon-botulinum toxin target cell. Such modifications to a targetingdomain result in a modified toxin that is able to selectively bind to anon-botulinum toxin receptor (target receptor) present on anon-botulinum toxin target cell (re-targeted). A modified botulinumtoxin with a targeting activity for a non-botulinum toxin target cellcan bind to a receptor present on the non-botulinum toxin target cell,translocate into the cytoplasm, and exert its proteolytic effect on theSNARE complex of the target cell. In essence, a botulinum toxin lightchain comprising an enzymatic domain is intracellularly delivered to anydesired cell by selecting the appropriate targeting domain.

In some embodiments, the clostridial derivative is a botulinum toxin,which is selected from the group consisting of botulinum toxin types A,B, C₁, D, E, F and G. In one embodiment, the clostridial derivative ofthe present method is a botulinum toxin type A. The botulinum toxin canbe a recombinant botulinum neurotoxin, such as botulinum toxins producedby E. coli.

The clostridial derivative, such as a botulinum toxin, for use accordingto the present invention can be stored in lyophilized, vacuum dried formin containers under vacuum pressure or as stable liquids. Prior tolyophilization the botulinum toxin can be combined with pharmaceuticallyacceptable excipients, stabilizers and/or carriers, such as, forexample, albumin, or the like. Acceptable excipients or stabilizersinclude protein excipients, such as albumin or gelatin, or the like, ornon-protein excipients, including poloxamers, saccharides, polyethyleneglycol, or the like. In embodiments containing albumin, the albumin canbe, for example, human serum albumin or recombinant human albumin, orthe like. The lyophilized material can be reconstituted with a suitableliquid such as, for example, saline, water, or the like to create asolution or composition containing the botulinum toxin to beadministered to the patient.

In some embodiments, to increase the resident time of the clostridialderivative in the joint, the clostridial derivative is provided in acontrolled release system comprising a polymeric matrix encapsulatingthe clostridial derivative, wherein fractional amount of the clostridialderivative is released from the polymeric matrix over a prolonged periodof time in a controlled manner. Controlled release neurotoxin systemshave been disclosed for example in U.S. Pat. Nos. 6,585,993; 6,585,993;6,306,423 and 6,312,708, each of which is hereby incorporated byreference in its entirety.

The therapeutically effective amount of the clostiridial derivative, forexample a botulinum toxin, administered according to the present methodcan vary according to the potency of the toxin and particularcharacteristics of the condition being treated, including its severityand other various patient variables including size, weight, age, andresponsiveness to therapy. The potency of the toxin is expressed as amultiple of the LD₅₀ value for the mouse, one unit (U) of toxin beingdefined as being the equivalent amount of toxin that kills 50% of agroup of 18 to 20 female Swiss-Webster mice, weighing about 20 gramseach.

The therapeutically effective amount of the botulinum toxin according tothe present method can vary according to the potency of a particularbotulinum toxin, as commercially available Botulinum toxin formulationsdo not have equivalent potency units. For example, one unit of BOTOX®(onabotulinumtoxinA), a botulinum toxin type A available from Allergan,Inc., has a potency unit that is approximately equal to 3 to 5 units ofDYSPORT® (abobotulinumtoxinA), also a botulinum toxin type A availablefrom Ipsen Pharmaceuticals. In some embodiments, the amount ofabobotulinumtoxinA, (such as DYSPORT®), administered in the presentmethod is about three to four times the amount of onabotulinumtoxinA(such as BOTOX®) administered, as comparative studies have suggestedthat one unit of onabotulinumtoxinA has a potency that is approximatelyequal to three to four units of abobotulinumtoxinA. MYOBLOC®, abotulinum toxin type B available from Elan, has a much lower potencyunit relative to BOTOX®. In some embodiments, the botulinum neurotoxincan be a pure toxin, devoid of complexing proteins, such as XEOMIN®(incobotulinumtoxinA). One unit of incobotulinumtoxinA has potencyapproximately equivalent to one unit of onabotulinumtoxinA. The quantityof toxin administered and the frequency of its administration will be atthe discretion of the physician responsible for the treatment and willbe commensurate with questions of safety and the effects produced by aparticular toxin formulation.

In some embodiments, the present method comprises administering atherapeutically effective amount of the clostridial derivative to theosteoarthritis-affected site. In some embodiments, the therapeuticallyeffective amount is administered in multiples treatment sessions. Insome embodiments, the therapeutically effective amount is administeredper treatment session.

In some embodiments, the therapeutically effective amount ranges fromabout 2 units to about 800 units of a botulinum toxin type A, such asonabotulinumtoxinA (such as BOTOX®). In some embodiments, thetherapeutically effective amount ranges from 10 units to about 100 unitsof onabotulinumtoxinA. In some embodiments, the therapeuticallyeffective amount ranges from about 150 to about 300 units ofonabotulinumtoxinA. In one embodiment, the therapeutically effectiveamount is about 200 units of onabotulinumtoxinA. In some embodiments,the therapeutically effective amount ranges from about 300 to about 500units of onabotulinumtoxinA. In one embodiment, the therapeuticallyeffective amount is about 400 units of onabotulinumtoxinA. In someembodiments, the therapeutically amount ranges from about 500 units toabout 800 units of onabotulinumtoxinA.

In some embodiments, the therapeutically effective amount ofabobotulinumtoxinA, (such as DYSPORT®), administered according toaspects of the present method is about three to four times the amount ofonabotulinumtoxinA (such as BOTOX®). In some embodiments, thetherapeutically effective amount of incobotulinumtoxinA, (such asXEOMIN®), administered according to aspects of the present method issimilar to the amount of onabotulinumtoxinA (such as BOTOX®)administered, as comparative studies have suggested that one unit ofincobotulinumtoxinA has a potency approximately equivalent to one unitof onabotulinumtoxinA.

In some embodiments, the therapeutically effective amount is from about0.1 to 1000 micrograms (μg) of a TEM (Targeted Exocytosis Modulators).

In some embodiments, the present method comprises administering fromabout 2 to about 800 units of a botulinum toxin type A, such as BOTOX®,intra-articularly into a joint space, such as for example a knee joint.In some embodiments, the present method comprises administering 50-250units of onabotulinumtoxinA, such as BOTOX®, intra-articularly into ajoint space. In one specific embodiment, the present method comprisesadministering about 200 units of a botulinum toxin type Aintra-articularly into a joint space. In one specific embodiment, thepresent method comprises administering about 400 units of a botulinumtoxin type A intra-articularly into a joint space. In some embodiments,the present method comprises administering about 10-500 units of abotulinum toxin type A into a fat pad, such as the infra-patellar fatpad, the supra-patellar fat pad, or combinations thereof. In onespecific embodiment, the present method comprises administering about10-500 units of a botulinum toxin type A intra-articularly into a jointspace and about 10-500 units into a fat pad, such as the infra-patellarfat pad, the supra-patellar fat pad, or combinations thereof. Inalternative embodiments, the present method comprises administeringabout 40-1200 units of DYSPORT® intra-articularly into a joint space andabout 40-2000 units of DYSPORT® into a fat pad, such as theinfra-patellar fat pad, the supra-patellar fat pad, or combinationsthereof. In some embodiments, the present method comprises administeringa botulinum toxin type A, and concurrently or sequentially administeringa botulinum toxin type B, C₁, D, E, F, G, or combinations thereof. Inalternative embodiments, the present method comprises administering abotulinum toxin type B, C₁, D, E, F, G, or combinations thereof.

In some embodiments, the present method comprises administering about0.1 to 1000 micrograms (μg) of a TEM (Targeted Exocytosis Modulators)intra-articularly into a joint space, such as for example a knee joint.In some embodiments, the present method comprises administering about20-250 μg of TEM intra-articularly into a joint space. In one specificembodiment, the present method comprises administering about 3-70 μg ofTEM intra-articularly into a joint space. In some embodiments, thepresent method comprises administering about 0.1 to 1000 μg of a TEMinto a fat pad, such as the infra-patellar fat pad, the supra-patellarfat pad, or combinations thereof. In one specific embodiment, thepresent method comprises administering about 0.1 to 1000 μg of a TEMintra-articularly into a joint space and about 0.1 to 1000 μg into a fatpad, such as the infra-patellar fat pad, the supra-patellar fat pad, orcombinations thereof.

The effects of the present method can persist for between about 1 monthand 5 years. Administration can be modified according to the changes inOA-associated symptoms. In some embodiments, administration of aclostridial derivative according to aspects of the present method iscarried out from about 3 months to about 6 months. In some embodiments,increased efficacy of the treatment accorded to the present method isexpected to happen when the clostridial derivative is administeredaccording to the disclosed method at about 3 month intervals. Inalternative embodiments, the present method can be repeated every 6months, or 12 months, or 18 months according to progression ofosteoarthritis.

In some embodiments, in addition to administering a therapeuticallyeffective amount of a clostridial derivative to an OA-affected site, thepresent method further comprises administering corticosteroids and/orviscosupplements to the OA-affected site. Corticosteroids suitable forthe present method includes methylprednisone acetate (DEPO-MEDROL),triamcinolone acetate (KENALOG 10, KENALOG 40), triamcinolonehexacetonide (ARISTOSPAN).Viscosupplements suitable for the presentmethod include hyaluronate formulations, such as ADANT®, SYNOCROM® orSYNVISC®. The corticosteroids and/or viscosupplements can beadministered concurrently, prior to and/or subsequent to theadministration of the clostridial derivative. Viscosupplementsadministration to restore elastoviscosity of the joint (dosage,frequency, and mode) can be carried out as well known to one of ordinaryskill in the art.

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat or alleviateosteoarthritis-associated symptoms within the scope of the presentdisclosure, and it is not intended to limit the scope of the invention.In the following examples various modes of non-systemic administrationof a botulinum neurotoxin can be carried out. For example, byintramuscular injection, non-intramuscular injection, intra-articularinjection, extra-articular injection, peri-articular injection,subcutaneous injection or by implantation of a controlled releaseimplant.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat conditions within thescope of embodiments of the present invention and are not intended tolimit the scope of the invention.

Example 1—Botulinum Toxin Therapy for Osteoarthritis (OA) Knee Pain

A double-blind, placebo-controlled, randomized study was performed toevaluate the efficacy of a single intra-articular (IA) injection of abotulinum toxin Type A (such as BOTOX®) compared with placebo fortreatment for primary idiopathic knee osteoarthritis (OA)(Kellgren-Lawrence (KL) grade I, II or III). Participants were men orwomen aged 40 to 75 years (N=121).

The patients were randomized in the treatment group or the placebogroup. Two analysis populations were defined: the safety population andintent-to-treat (ITT) population. The safety population consisted of allpatients who received at least 1 injection of the study treatment. Forthe safety population, patients were analyzed according to actualtreatment received at the study treatment visit, regardless ofrandomization assignment. The ITT population consisted of all randomizedpatients, whether treated or not. For the ITT population, patients wereto be analyzed according to randomization assignment, regardless ofactual treatment received. The safety population was used for analysisof safety variables, as well as efficacy variables and for othervariables that were not safety variables.

There were no clinically relevant differences in baselinecharacteristics. Mean age 62.3 years, 51% female, all Caucasian, KLI=9.1%: KL II=62%; KL III=28.9%.

At the baseline, the patients were given a PainDETECT questionnaire(PD-Q). An exemplary questionnaire is shown in table 1. The total score(range from −1 to 38) was calculated from the sum of score to ninequestions. The Baseline PainDETECT scores were used post-hoc to classifypatients into three groups. The following cut-off points were used:

Score ≤12: nociceptive pain (neuropathic component unlikely)Score 13-18: neuropathic pain possibleScore ≥19: neuropathic pain (nerve lesion or dysfunction likely)

Study design: For the treatment group, a single 200 U dose of abotulinum toxin Type A (BOTOX®) was injected into the intra-articularspace of the knee on Day 1. For the placebo group, a single dose ofnormal saline was injected into the intra-articular space of the studyknee on Day 1.

The primary efficacy variable was the change from baseline of theaverage over 14 days of the daily worst pain score. The 14-day averagescore was derived from daily scores recorded in a diary for worst painin the study knee. Cumulative 14-day pain scores were prorated orimputed if necessary, with the average calculated from the cumulativescores.

The ssecondary efficacy variables included change from baseline in theWestern Ontario McMaster (WOMAC) Osteoarthritis Index and change inbaseline in the patient global impression of change (patient-GIC). Thefollowing scores from the WOMAC were obtained at the baseline and ateach follow-up visit: Total Index Score; Pain Score, Physical FunctionScore.

The Patient-GIC is a questionnaire used by the patient to provide aglobal impression of change in their health status since enrollment,whether or not in the patient's judgment a change was related to thestudy treatment. The patient-GIC score was obtained at each follow-upvisit, which is a change from baseline by definition on a −3 and +3scale. Response on the patient-GIC was on a −3 to +3 scale of very muchworse, much worse, minimally worse, no change, minimally improved, muchimproved, and very much improved. Negative scores indicate worsening andpositive scores indicate improvement. Responder analyses were performedon patient-GIC by visit at weeks 1, 4, 8, and 12. A patient wasconsidered a responder at a particular visit if the response of thepatient-GIC was ‘much improved’ or ‘very much improved’ at that visit.

Other efficacy measurements included: physician global impression ofchange (physician-GIC), rescue medication count and PainDETECTQuestionnaire (PD-Q), knee synovial fluid effusion biomarkerconcentrations and pain models.

Rescue Medication Count: Rescue medication cumulative count, per 14-daybaseline and changes from baseline to the 14-day periods ending witheach week starting with week 2 were analyzed. Each 14-day cumulativecount was derived from daily responses recorded in the diary regardingthe number of paracetamol tablets used.

Pain Model Evaluations:

There were 5 sets of efficacy variables derived from pain modelevaluations:

-   -   quantitative sensory testing (QST) of joint pain, as indicated        by pressure-pain threshold (PPT)    -   spreading sensitization, as indicated by PPT    -   spreading sensitization, as indicated by area of pain in the        knee    -   wind-up like pain, assessed on the study knee for the most        painful knee site    -   cuff algometry, involved 3 variables, the cuff pressure,        pressure-pain tolerance, and the pressure-pain limit, with each        of the 3 variables represented by the mean of 3 repeat        measurements.

Results: For the overall safety population, no significant difference inoutcome and pain relief between the treatment group and the placebogroup. The nociceptive patients (n=68) showed improved outcomes in thePPT pain model and wind-up like pain model, along with pain relieffollowing treatment with botulinum toxin type A (BOTOX®) versus placebo.

Since the safety population and the ITT population were identical inthis study, results are summarized for the safety population and areapplicable to the ITT population.

As shown in FIGS. 1 and 3B, For the overall safety population, nostatistically significant difference between the treatment group and theplacebo group was observed in the daily worst pain score.

As shown in FIGS. 2 and 4B, for the overall safety population, nostatistically significant differences were observed between thetreatment group and the placebo group in the change from baseline in theWOMAC Pain scores. Similarly, for the overall safety population, nostatistically significant differences between the treatment group andthe placebo group were observed in the change from baseline in the WOMACtotal index score, WOMAC physical function score.

As shown in FIG. 5B, for the overall safety population, no statisticallysignificant differences were observed between the treatment group andthe placebo group in the patient-GIC responder. Even though nostatistically significant differences were observed between thetreatment and the placebo groups in the GIC-responder rate in the safetypopulation, the responder rate was higher in the treatment group than inthe placebo group at weeks 1, 8, and 12. The responder rates at weeks 8and 12 were 29/59 (49.2%) and 28/59 (47.5%), respectively, in thetreatment group and were 22/59 (37.3%) and 22/60 (36.7%), respectively,in the placebo group.

Of the 121 patients in the safety population, 68 patients were in thenociceptive pain subgroup; 36 patients in the BOTOX group and 32patients in the placebo group. The demographics and baselinecharacteristics of the nociceptive pain subgroup were similar to thesafety population with no clinically relevant or statisticallysignificant differences observed between the treatment groups. In thenociceptive pain subgroup, the mean age of patients was 62.0 years (62.3years in the safety population), 51.5% (35/68) were in the 40 to 64years age subgroup, and 48.5% (33/68) were in the ≥65 years agesubgroup.

As shown in FIG. 3A, for the nociceptive pain subgroup, at any timepoint, the treatment group had a numerically greater (improvement) meanchange from baseline than the placebo group.

As shown in FIG. 4A, in the nociceptive pain subgroup, the mean (SD)WOMAC pains cores at baseline were 22.7 (5.95) and 22.9 (6.98) in thetreatment and placebo groups, respectively. At the follow up visitsweeks 1, 4, 8 and 12, there was a decrease (improvement) in the WOMACpain score in both treatment and placebo groups. The decrease in WOMACpain score was numerically greater in the treatment group than in theplacebo group at all follow-up visits and statistically significantlygreater at week 8 (p=0.021).

As shown in FIGS. 5A and 5B, the difference in patient-GIC responderswas more significant between the treatment versus placebo groups in thenociceptive patient population relative to the overall safetypopulation. Indeed, the differences in the patient-GIC respondersbetween the treatment group and the placebo group in the overall safetypopulation for weeks 1, 4, 8 and 12 were 27%, −12%, 32% and 29%respectively. In contrast, for the nociceptive patient group, as shownin FIG. 5A, the differences in patient-GIC score between the treatmentgroup and the placebo group in the total population for weeks 1, 4, 8and 12 were 56%, −8%, 77% and 106%, respectively.

As shown in FIG. 6B, the mean reduction from baseline in number ofmedication days per 14-day period was greater in the BOTOX group than inthe placebo group at all weeks. Statistically significant between groupdifferences in favor of BOTOX were observed from week 9 to week 12 inthe mean change from baseline in medication days per 14-day period. Asshown in FIGS. 6A and 6B, the difference in Rescue Medication CumulativeCount was more significant between the treatment group versus placebo inthe nociceptive patient subgroup, versus the overall safety population.

Example 2: Effect of Botulinum Toxin Type A (BOTOX®) Treatment on OAKnee Pain

A 42 year old male, with a body weight of 86 kg and a height of 1.82 m,had been suffering from left knee pain for over 4 years. He wasdiagnosed with knee osteoarthritis, without any apparent knee trauma orsurgery. Administrations of acetaminophen and NSAIDs failed to alleviatethe pain, which severely limited his activities. X-ray rating showedthat this patient's knee joint had Kellgren-Lawrence score of I(indicating formation of osteophytes on the tibial spines). He expressedhis willingness to participate in a BOTOX knee osteoarthritis trial. Hismean daily worst pain was 7.8 numerical rating scale (or NRS) for the14-day period prior to treatment. The patient was provided a painDETECTquestionnaire at the screening. The score of his questionnaire was foundto be 11.

The patient was treated with 200 units of a botulinum toxin Type A(BOTOX®) by intra-articularly injection in the knee joint underultra-sound guidance.

The patient did not have any discomfort post injection. After one week,the patient reported that his knee pain via NRS was reduced from 7.8 to6.3. His pain continued to improve, by the end of the 12 week study herated his knee pain as 2.0 on the NRS; thus his total NRS pain reductionwas 5.8. It has been established that a NRS improvement of at least 2.0is clinical meaningful. He also reported that with the pain alleviated,he was able to resume his daily activities with much less limitation.

Example 3

A 47 year old female, with a body weight of 87 kg and a height of 1.6 m,had been suffering from left knee pain for over 4 years. She wasdiagnosed with idiopathic knee osteoarthritis. She had been treated withNSAIDs, intra-articular steroids or hyaluronic injections. However,these treatments failed to provide sufficient pain relief and functionalimprovement. She was willing to participate in the knee OA clinicaltrial. Her mean daily worst pain score was 5.9 NRS at baseline (the meanof 14-day pain scores). She was also provided a PainDETECTquestionnaire. Her total score to the questionnaire was found to be 12.

She was treated with about 200 units of a botulinum toxin Type A(BOTOX®) into the knee joint by intra-articular injection. No postinjection discomfort was reported. After one week, the patient reportedpain relief, her pain rating was 4.6 via NRS. After the 12 week study,her pain score was 3.6 via NRA by the end of the study with a total painreduction of 2.3. It has been established that a NRS improvement of atleast 2.0 is clinical meaningful.

Example 4

An active 34-year-old female who plays women ice hockey and is an avidweekend cyclist presents with right knee pain. Her physical therapisthas used a variety of techniques including manipulation and stretches,which fail to resolve the pain. She takes simple anti-inflammatorymedication to ease the pain; however they provide little relief. Herbaseline NRS pain score is 7.0. She is provided with a PainDETECTQuestionnaire to categorize her pain. Her total score is 10. She isdetermined to be treatment-susceptible. She is treated with 250 μg of aTEM intra-articularly into the knee joint. After one week, the symptomsstarted to improve with significant improvement observed at week 12. Herpost-treatment NRS pain scores are reduced by 5.0 points, with a posttreatment score at week 12 of 2.0 NRS. It has been established that aNRS improvement of 2.0 is clinical meaningful.

Example 6

A 57 year old mechanic reports to his doctor that pain due to thearthritis in his 1^(st) carpometacarpal (CMC) joints of both hands andthe base of the thumb joint cannot be flexed. The pain is becomingunbearable, and rates his pain at a 9 on the numerical rating scale(NRS) for pain at the doctor's office. Application of various topicalcreams that contain ingredients such as methyl salicylate, menthol andcapsaicin are ineffective. The physician provides him with aquestionnaire to categorize his pain and to determine whether he wouldbe responsive to a botulinum toxin treatment. His total score is 8,which is deemed to be treatment-eligible. The physician decides toadminister a botulinum toxin type A in order to treat the arthritis.

Upon ultrasound inspection, it is observed that effusion accumulates inthe right 1^(st) CMC joint, which was withdrawn and stored at −80° C.The doctor administers a total of 100 units of a botulinum toxin type A(BOTOX®) as follows: about 50 units into the right and left 1^(st) CMCjoint cavity, respectively. After about 8 days, the patient reports thathis arthritic pain is alleviated and ranks his pain at only a 2 on thesame NRS. The arthritic pain remains alleviated for about at least about3 months. There is no muscle weakness in his hands. He can use his handsfor daily work now.

Example 7

A 39 year old female long distance runner (and known osteoarthritissufferer) complains to her family doctor that her hip joints ache mostof the time, and that her running regimen is being hampered by the pain,rating as an 8 on the doctor's NRS for pain. X-ray shows that her lefthip joint space has moderate narrowing comparing with the right hipjoint. She is diagnosed as hip osteoarthritis in both joints. Aftertaking NSAIDs for 2 months, the patient reports that no improvement oralleviation of the pain. The physician provides her with a questionnaireto categorize the pain and to determine whether she would be responsiveto a botulinum toxin treatment. The total score is 10, the patient isdeemed to be treatment-eligible.

The doctor decides to treat the arthritis pain by administration of abotulinum toxin into hip joints. About 300 units of abobotulinumA (suchas DYSPORT®) are bilaterally injected, i.e. about 150 units into theleft and right hip cavity in 2 mL normal saline. After 10 days, thepatient reports returns to the doctor's office for a follow up andreports that the pain in her hips is alleviated, and now when asked torate her pain, she rates it as a 3, a good and desirable improvement.The patient is similarly administered the botulinum toxin every 6 monthsthereafter. She can now resume her running activity. Her left hip jointspace recovers to the normal level as her right hip joint space afterbotulinum toxin treatments.

Many alterations and modifications may be made by those having ordinaryskill in the art, without departing from the spirit and scope of thedisclosure. Therefore, it must be understood that the describedembodiments have been set forth only for the purposes of examples, andthat the embodiments should not be taken as limiting the scope of thefollowing claims. The following claims are, therefore, to be read toinclude not only the combination of elements which are literally setforth, but all equivalent elements for performing substantially the samefunction in substantially the same way to obtain substantially the sameresult. The claims are thus to be understood to include those that havebeen described above, those that are conceptually equivalent, and thosethat incorporate the ideas of the disclosure.

We claim:
 1. A method for treating or alleviating osteoarthritis(OA)-associated pain in a patient in need thereof, the method comprisinglocally administering a therapeutically effective amount of aclostridial derivative to an osteoarthritis-affected site of the OApatient, thereby treating or alleviating the osteoarthritis-associatedpain in the patient, wherein the therapeutically effective amount isfrom about 200 units to about 800 units, and wherein the clostridialderivative is a botulinum toxin type A.
 2. The method of claim 1,wherein the osteoarthritis-affected site is selected from the groupconsisting of a knee joint, a hip joint, a hand joint, a shoulder joint,an ankle joint, a foot joint, an elbow joint, a wrist joint, asacroiliac joint, a spine joint, and combinations thereof.
 3. The methodof claim 1, wherein the administering is by intra-articular injectioninto a joint space.
 4. The method of claim 1, wherein the clostridialderivative is onabotulinumtoxinA.
 5. The method of claim 4, wherein thetherapeutically effective amount ranges from about 300 to about 500units of onabotulinumtoxinA.
 6. The method of claim 5, wherein thetherapeutically effective amount is about 400 units.
 7. The method ofclaim 1, wherein the clostridial derivative is incobotulinumtoxinA. 8.The method of claim 7, wherein the therapeutically effective amountranges from about 300 to about 500 units of incobotulinumtoxinA.
 9. Themethod of claim 8, wherein the therapeutically effective amount is about400 units.
 10. The method of claim 1, wherein the patient's pain iscategorized as nociceptive.